{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T13:58:20Z","timestamp":1781013500330,"version":"3.54.1"},"reference-count":24,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2024,4,12]],"date-time":"2024-04-12T00:00:00Z","timestamp":1712880000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The p.Arg301Gln variant in the \u03b1 -galactosidase A gene (GLA) has been poorly described in the literature. The few reports show controversial information, with both classical and nonclassical Anderson\u2013Fabry Disease (AFD) presentation patterns. The aim of this study was to analyze the penetrance, clinical phenotype, and biochemical profile of an international cohort of patients carrying the p.Arg301Gln genetic variant in the GLA gene. This was an observational, international, and retrospective cohort case series study of patients carrying the p.Arg301Gln variant in the GLA gene associated with AFD disease. Forty-nine p.Arg301Gln GLA carriers, 41% male, were analyzed. The penetrance was 63% in the entire cohort and 1.5 times higher in men. The mean age of symptoms onset was 41 years; compared to women, men presented symptoms earlier and with a shorter delay to diagnosis. The typical clinical triad\u2014cornea verticillate, neuropathic pain, and angiokeratomas\u2014affected only 20% of the cohort, with no differences between genders. During follow-up, almost 20% of the patients presented some type of nonfatal cardiovascular and renal event (stroke, need for dialysis, heart failure, and arrhythmias requiring intracardiac devices), predominantly affecting men. Residual levels were the most common finding of \u03b1-GAL A enzyme activity, only a few women had a normal level; a small proportion of men had undetectable levels. The incidence of combined outcomes including all causes of death was 33%, and the cumulative incidence of all-cause mortality was 9% at the follow-up. Patients carrying the p.Arg301Gln GLA variant have a high penetrance, with predominantly cardiorenal involvement and clinical onset of the disease in middle age. Only a small proportion showed the classic clinical presentation of AFD. As in other X-linked diseases, males were more affected by severe cardiovascular and renal events. This genotype\u2013phenotype correlation could be useful from a practical clinical point of view and for future decision making.<\/jats:p>","DOI":"10.3390\/ijms25084299","type":"journal-article","created":{"date-parts":[[2024,4,12]],"date-time":"2024-04-12T11:09:20Z","timestamp":1712920160000},"page":"4299","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Phenotypic Expression and Outcomes in Patients with the p.Arg301Gln GLA Variant in Anderson\u2013Fabry Disease"],"prefix":"10.3390","volume":"25","author":[{"given":"Roc\u00edo","family":"Blanco","sequence":"first","affiliation":[{"name":"Cardiology Department, Hospital Universitario Son Llatzer, 07198 Palma de Mallorca, Spain"},{"name":"Cardiology Department, Italian Hospital of Buenos Aires, Buenos Aires C1199ABB, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yolanda","family":"Rico-Ram\u00edrez","sequence":"additional","affiliation":[{"name":"Cardiology Department, Hospital Universitario Son Espases, 07120 Palma de Mallorca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3757-262X","authenticated-orcid":false,"given":"\u00c1lvaro","family":"Hermida-Ameijeiras","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Clinical University Hospital of Santiago de Compostela, 15706 Santiago de Compostela, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8819-5492","authenticated-orcid":false,"given":"Israa Mahmoud Sanad","family":"Abdullah","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Clinical Nutrition, University Hospital Zurich, 8091 Zurich, Switzerland"},{"name":"Division of Internal Medicine, Psychiatric University Hospital Zurich, 8008 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4317-8824","authenticated-orcid":false,"given":"Kolja","family":"Lau","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, University Hospital W\u00fcrzburg, 97080 W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge","family":"Alvarez-Rubio","sequence":"additional","affiliation":[{"name":"Cardiology Department, Hospital Universitario Son Llatzer, 07198 Palma de Mallorca, Spain"},{"name":"The Health Research Institute of the Balearic Islands (IdISBa), 07120 Palma de Mallorca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Fortuny","sequence":"additional","affiliation":[{"name":"Cardiology Department, Hospital Universitario Son Espases, 07120 Palma de Mallorca, Spain"},{"name":"The Health Research Institute of the Balearic Islands (IdISBa), 07120 Palma de Mallorca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4379-140X","authenticated-orcid":false,"given":"Amparo","family":"Mart\u00ednez-Monzon\u00eds","sequence":"additional","affiliation":[{"name":"Cardiology Department, Clinical University Hospital of Santiago de Compostela, 15706 Santiago de Compostela, Spain"},{"name":"Centro de Investigaci\u00f3n en Red de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4119-5516","authenticated-orcid":false,"given":"Albina","family":"Nowak","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Clinical Nutrition, University Hospital Zurich, 8091 Zurich, Switzerland"},{"name":"Division of Internal Medicine, Psychiatric University Hospital Zurich, 8008 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2560-4068","authenticated-orcid":false,"given":"Peter","family":"Nordbeck","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, University Hospital W\u00fcrzburg, 97080 W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Veras-Burgos","sequence":"additional","affiliation":[{"name":"Cardiology Department, Hospital Universitario Son Llatzer, 07198 Palma de Mallorca, Spain"},{"name":"The Health Research Institute of the Balearic Islands (IdISBa), 07120 Palma de Mallorca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaume","family":"Pons-Llinares","sequence":"additional","affiliation":[{"name":"Cardiology Department, Hospital Universitario Son Espases, 07120 Palma de Mallorca, Spain"},{"name":"The Health Research Institute of the Balearic Islands (IdISBa), 07120 Palma de Mallorca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8930-9738","authenticated-orcid":false,"given":"Emiliano","family":"Rossi","sequence":"additional","affiliation":[{"name":"Cardiology Department, Italian Hospital of Buenos Aires, Buenos Aires C1199ABB, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0657-0306","authenticated-orcid":false,"given":"Fiama","family":"Caimi-Mart\u00ednez","sequence":"additional","affiliation":[{"name":"Cardiology Department, Hospital Universitario Son Llatzer, 07198 Palma de Mallorca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa","family":"Bosch-Rovira","sequence":"additional","affiliation":[{"name":"Cardiology Department, Hospital Universitario Son Espases, 07120 Palma de Mallorca, Spain"},{"name":"The Health Research Institute of the Balearic Islands (IdISBa), 07120 Palma de Mallorca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Alamar-Cervera","sequence":"additional","affiliation":[{"name":"Cardiology Department, Hospital Universitario Son Llatzer, 07198 Palma de Mallorca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6032-2090","authenticated-orcid":false,"given":"Virginia","family":"Ruiz-Pizarro","sequence":"additional","affiliation":[{"name":"Cardiology Department, Hospital Universitario Son Llatzer, 07198 Palma de Mallorca, Spain"},{"name":"The Health Research Institute of the Balearic Islands (IdISBa), 07120 Palma de Mallorca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8739-6081","authenticated-orcid":false,"given":"Laura","family":"Torres-Juan","sequence":"additional","affiliation":[{"name":"The Health Research Institute of the Balearic Islands (IdISBa), 07120 Palma de Mallorca, Spain"},{"name":"Molecular Diagnostics and Clinical Genetics Unit, Hospital Universitario Son Espases, 07120 Palma de Mallorca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9374-1219","authenticated-orcid":false,"given":"Damian","family":"Heine-Su\u00f1er","sequence":"additional","affiliation":[{"name":"The Health Research Institute of the Balearic Islands (IdISBa), 07120 Palma de Mallorca, Spain"},{"name":"Molecular Diagnostics and Clinical Genetics Unit, Hospital Universitario Son Espases, 07120 Palma de Mallorca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9222-325X","authenticated-orcid":false,"given":"Tom\u00e1s","family":"Ripoll-Vera","sequence":"additional","affiliation":[{"name":"Cardiology Department, Hospital Universitario Son Llatzer, 07198 Palma de Mallorca, Spain"},{"name":"The Health Research Institute of the Balearic Islands (IdISBa), 07120 Palma de Mallorca, Spain"},{"name":"Biomedical Research Networking Center for Physiopathology of Obesity and Nutrition (CIBEROBN), Carlos III Health Institute, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1111\/j.1651-2227.2007.00198.x","article-title":"Structure-function relationships in alpha-galactosidase A","volume":"96","author":"Garman","year":"2007","journal-title":"Acta Paediatr."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1111\/cge.14102","article-title":"Challenging the traditional approach for interpreting genetic variants: Lessons from Fabry disease","volume":"101","author":"Germain","year":"2022","journal-title":"Clin. 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